161715-21-5

Basic information

• Product Name: Tebipenem
• Synonyms: Tebipenem;(4R,5S,6S)-3-[[1-(4,5-Dihydro-2-thiazolyl)-3-azetidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;LJC 11036;LJC11036;LJC-11036;Tebipenem Impurity 5
• CAS NO: 161715-21-5
• Molecular Formula: C₁₆H₂₁N₃O₄S₂
• Molecular Weight: 383.48564
• EINECS: -0
• Product Categories: API
• Mol File: 161715-21-5.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 624.5±65.0 °C(Predicted)
• Appearance: /
• Density: 1.75
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: insoluble in EtOH; ≥19.15 mg/mL in H2O with gentle warming; ≥24.9 mg/mL in DMSO
• PKA: 4.29±0.60(Predicted)
• CAS DataBase Reference: Tebipenem(CAS DataBase Reference)
• NIST Chemistry Reference: Tebipenem(161715-21-5)
• EPA Substance Registry System: Tebipenem(161715-21-5)

Safety Data

• Hazardous Substances Data: 161715-21-5(Hazardous Substances Data)

Usage

Biological Activity

tebipenem is an orally available carbapenem antibiotic. tebipenem is active against a panel of clinical isolates from a variety of bacterial species (mic50s ≤ 0.0039 ~ 8 μg/ml), including methicillin-resistant strains of staphylococcus aureus (s. aureus) and staphylococcus epidermidis (s. epidermidis), as well as penicillin-resistant streptococcus pneumoniae (s. pneumonia). tebipenem also inhibits β-lactamase in a time- and concentration-dependent manner. tebipenem pivoxil, a derivative of tebipenem, has been under development as the first orally available carbapenem antibiotic for the treatment of respiratory and otolaryngological infections caused by drug-resistant s. pneumonia in pediatric patients.1. hazra s, xu h, blanchard js. tebipenem, a new carbapenem antibiotic, is a slow substrate that inhibits the β-lactamase from mycobacterium tuberculosis. biochemistry, 2014, 53(22): 3671-3678.2. fujimoto k, takemoto k, hatano k, et al. novel carbapenem antibiotics for parenteral and oral applications: in vitro and in vivo activities of 2-aryl carbapenems and their pharmacokinetics in laboratory animals. antimicrobial agents and chemotherapy, 2013, 57(2): 697-707.

Synthetic route

(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-{[1-(2-thiazolin-2-yl)-3-azetidinyl]mercapto}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester (161715-20-4) → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
With hydrogen In water; butan-1-ol at 20℃; under 15001.5 Torr; for 4h; Solvent; Pressure; Reagent/catalyst;	94.5%
With 0.5% Pd/C; hydrogen; sodium hydrogencarbonate In water; butan-1-ol at 25 - 30℃; under 7500.75 Torr; for 3h; Reagent/catalyst;	89.3%
With sodium hydrogencarbonate; palladium on activated charcoal In water; butan-1-ol at 20℃; under 3000.24 Torr; for 1.5h;	82%

C19H25N3O4S2 → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; sodium hydrogencarbonate In water at 13℃; under 11251.1 Torr; for 2.5h; Large scale;	78.9%

(4R,5S,6S)-3-((1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carbonyl 4-nitrobenzoate → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; sodium hydrogencarbonate In water; butan-1-ol at 20℃; under 3000.3 - 3750.38 Torr; for 7h; Solvent; Pressure; Temperature;	77%
With 2,6-dimethylpyridine; palladium 10% on activated carbon; hydrogen In water at 20℃; under 13501.4 Torr; for 4.5h; Reagent/catalyst; Pressure; Temperature; Time; Large scale;	75.7%

3-methanesulfonyloxy-1-(1,3-thiazolin-2-yl)azetidine (179337-62-3) → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 88 percent / potassium thioacetate / dimethylformamide / 5.5 h / 100 °C 2.1: KOH / propan-2-ol; methanol / 0.17 h / 5 °C 2.2: 87 percent / HCl / propan-2-ol; methanol / 15 h / 5 °C 3.1: 94 percent / diisopropyl ethylamine; MeCN / 2 h / -20 °C 4.1: 82 percent / sodium hydrogen carbonate / Pd-C / butan-1-ol; H2O / 1.5 h / 20 °C / 3000.24 Torr View Scheme

1-(1,3-thiazolin-2-yl-)azetidin-3-ol (161715-27-1) → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 93 percent / DMAP; Et3N / tetrahydrofuran / 0.5 h / 5 °C 2.1: 88 percent / potassium thioacetate / dimethylformamide / 5.5 h / 100 °C 3.1: KOH / propan-2-ol; methanol / 0.17 h / 5 °C 3.2: 87 percent / HCl / propan-2-ol; methanol / 15 h / 5 °C 4.1: 94 percent / diisopropyl ethylamine; MeCN / 2 h / -20 °C 5.1: 82 percent / sodium hydrogen carbonate / Pd-C / butan-1-ol; H2O / 1.5 h / 20 °C / 3000.24 Torr View Scheme

3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine (161715-28-2) → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: KOH / propan-2-ol; methanol / 0.17 h / 5 °C 1.2: 87 percent / HCl / propan-2-ol; methanol / 15 h / 5 °C 2.1: 94 percent / diisopropyl ethylamine; MeCN / 2 h / -20 °C 3.1: 82 percent / sodium hydrogen carbonate / Pd-C / butan-1-ol; H2O / 1.5 h / 20 °C / 3000.24 Torr View Scheme

1-(4,5-dihydro-1,3-thiazol-2-yl)-3-mercaptoazetidine hydrochloride → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 94 percent / diisopropyl ethylamine; MeCN / 2 h / -20 °C 2: 82 percent / sodium hydrogen carbonate / Pd-C / butan-1-ol; H2O / 1.5 h / 20 °C / 3000.24 Torr View Scheme
Multi-step reaction with 2 steps 1.1: acetonitrile / 0.17 h / 20 °C 1.2: 10 h / -20 °C 2.1: hydrogen; sodium hydrogencarbonate; palladium 10% on activated carbon / butan-1-ol; water / 7 h / 20 °C / 3000.3 - 3750.38 Torr View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 3.5 h / -20 °C 2: 0.5% Pd/C; sodium hydrogencarbonate; hydrogen / butan-1-ol; water / 3 h / 25 - 30 °C / 7500.75 Torr View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile 2: hydrogen; water; palladium on activated charcoal / butan-1-ol View Scheme

(4R,5R,6S)-3-((diphenoxyphosphoryl)oxy)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carbonyl p-nitrobenzoate → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: acetonitrile / 0.17 h / 20 °C 1.2: 10 h / -20 °C 2.1: hydrogen; sodium hydrogencarbonate; palladium 10% on activated carbon / butan-1-ol; water / 7 h / 20 °C / 3000.3 - 3750.38 Torr View Scheme

(4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (93711-81-0, 90776-59-3) → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 3.5 h / -20 °C 2: 0.5% Pd/C; sodium hydrogencarbonate; hydrogen / butan-1-ol; water / 3 h / 25 - 30 °C / 7500.75 Torr View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile 2: hydrogen; water; palladium on activated charcoal / butan-1-ol View Scheme

C11H15NO5 + 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
Stage #1: C11H15NO5; 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride In 1,2-dichloro-ethane at -10℃; for 3h; 2-supported perfluorosulfonic acid resin pyridinium salt; Stage #2: 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 5℃; for 6h; Reagent/catalyst;	58.5 %Chromat.

(+)-(4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-(diphenylphosphoryloxy)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester → (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 0 °C 2: palladium 10% on activated carbon; hydrogen / ethyl acetate / 1 h / 30 °C View Scheme

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + iodomethyl pivaloate (53064-79-2) → L-084

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide for 0.5h; Large scale;	91.9%
With potassium carbonate In acetonitrile at 20℃;
Stage #1: (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid With caesium carbonate In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: iodomethyl pivaloate In N,N-dimethyl-formamide for 1h;

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + Chloromethyl pivalate (18997-19-8) → L-084

Conditions	Yield
Stage #1: (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 25℃; for 1h; Stage #2: Chloromethyl pivalate In water at 25℃; for 0.166667h;	89.7%
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	78%
Stage #1: Chloromethyl pivalate With potassium iodide In N,N-dimethyl-formamide at 60℃; for 3h; Stage #2: (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid With triethylbenzylammonium iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 8h; Reagent/catalyst;	61%
Stage #1: (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 1h; Large scale; Stage #2: Chloromethyl pivalate In N,N-dimethyl-formamide at 45℃; for 5h; Large scale;	1.05 kg

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + Chloromethyl pivalate (18997-19-8) → C22H31N3O6S2*ClH

Conditions	Yield
Stage #1: (4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; Chloromethyl pivalate With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 35℃; for 1h; Stage #2: With hydrogenchloride In water at 7 - 8℃; Time;	89.1%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + 1-methyl-cyclohexanecarboxylic acid chloromethyl ester → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 1-methyl-cyclohexanecarbonyloxymethyl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	88%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + 3-chloro-1(3H)-isobenzofuranone (6295-21-2) → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 3-oxo-1,3-dihydro-isobenzofuran-1-yl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	84%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + 4-methylbenzoic acid chloromethyl ester (70190-61-3) → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-methyl-benzoyloxymethyl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	84%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	82%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + chloromethyl p-chlorobenzoate (41657-97-0) → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-chloro-benzoyloxymethyl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	81%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + 4-methyl-cyclohexanecarboxylic acid chloromethyl ester → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-methyl-cyclohexanecarbonyloxymethyl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	80%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + chloromethyl 2-cyclohexylacetate → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid cyclohexylacetoxymethyl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	76%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + chloromethyl cyclohexanoic acid ester (29916-48-1) → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid cyclohexanecarbonyloxymethyl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	71%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + C28H43N3O9S2 → C44H62N6O12S4

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 10h;	66%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + 4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	54%

Upstream product

• 179337-57-6 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-mercaptoazetidine hydrochloride 
• 161715-20-4 (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-{[1-(2-thiazolin-2-yl)-3-azetidinyl]sulfanyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid-p-nitrobenzyl ester 
• 93711-81-0 (4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 
• 161715-28-2 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine 
• 161715-27-1 1-(1,3-thiazolin-2-yl-)azetidin-3-ol 
• 179337-62-3 3-methanesulfonyloxy-1-(1,3-thiazolin-2-yl)azetidine 

Downstream Products

• 161715-24-8 tebipenem 

Relevant articles and documents

Preparation method of medicinal tebipenem pivoxil

The invention discloses a preparation method of medicinal tebipenem pivoxil, which comprises the following steps: taking MAP and YKTP-1 as raw materials, sequentially carrying out condensation, reduction and substitution reaction, and purifying the material after the substitution reaction twice to obtain the medicinal tebipenem pivoxil. A primary purification process comprises the following steps: adding ethyl acetate into the material after the substitution reaction, conducting filtering, adding water into the filtrate, adjusting the pH value, carrying out liquid separation to obtain a water layer, adjusting the pH value of the water layer, conducting extracting with ethyl acetate to obtain an organic layer, washing the organic layer, conducting drying, decolorizing and filtering, carrying out vacuum concentration on the filtrate, conducting crystallizing and centrifuging, leaching a filter cake with ethyl acetate, and conducting drying in vacuum to obtain YKTP-4; and a secondary purification process comprises the following steps: mixing YKTP-4 with ethyl acetate, adding activated carbon, conducting stirring, conducting filtering to obtain filtrate, concentrating the filtrate to YKTP-4 under reduced pressure, conducting crystallizing and centrifuging, leaching a filter cake with ethyl acetate, and performing vacuum drying to obtain the medicinal tebipenem pivoxil.

Tebipenem pivoxil and synthetic method thereof

The invention provides tebipenem pivoxil and a synthetic method thereof. The invention relates to the technical field of drug synthesis. The synthetic method comprises the three-step synthetic reactions of condensation of a main ring and a tebipenem side chain, a TB-1 hydrogenation reduction reaction, and a reaction of a TB-2 intermediate and iodomethyl pivalate. The preparation method of tebipenem pivoxil provided by the invention is simple and convenient in preparation process, suitable for industrial production, and relatively high in yield; processing operations, such as column chromatography, which are required to be adopted by traditional synthesis are eliminated; a reasonable synthetic route is designed; the reaction time is effectively shortened; the post-processing process is simplified.

Preparation method of tebipenem pivoxil

The invention provides a preparation method of tebipenem pivoxil, and relates to the technical field of pesticide synthesis. The preparation method of the tebipenem pivoxil comprises the following steps that 1-(4,5-dihydro-2-thiazolyl) azetidine-3-thiol hydrochloride and 1 beta-methyl vinyl phosphate are used as raw materials to take a reaction under the existence of diisopropylethylamine, and an acetonitrile water solution is used for washing to obtain an intermediate I; the intermediate I, an n-butyl alcohol water solution, a palladium-carbon catalyst and sodium bicarbonate take a mixed reaction, and treatment is performed to obtain an intermediate II; the intermediate II and chloromethyl pivalate take a reaction through phase transfer catalyst catalysis under the existence of diisopropylethylamine and dimethylformamide to obtain an intermediate III; the intermediate III and a sodium bicarbonate water solution are mixed, ethyl acetate is added, and reaction and refining are performed to prepare the tebipenem pivoxil. The preparation method has the advantages that the purity and the yield of the intermediates are obviously improved; the purity of the final product of the tebipenem pivoxil reaches 99.21 to 99.78 percent; the yield reaches 88.7 to 92.1 percent.